Systemic High-dose Methotrexate Research Articles

A Case of CNS Lymphoma Imitating Post-Vaccination ADEM (P14-13.003)

<h3>Objective:</h3> NA <h3>Background:</h3> A previously healthy 42-year-old male presented acutely with slurred speech, confusion and urinary incontinence several weeks after receiving a COVID booster and Tdap vaccination. <h3>Design/Methods:</h3> NA <h3>Results:</h3> Initial workup revealed multifocal enhancing T2 white matter hyperintensities in the bilateral frontal/parietal lobes, corpus callosum and bilateral midbrain, sparing the cerebellum and spinal cord. Contrast enhanced CT of the chest, abdomen and pelvis showed no masses or lymphadenopathy. Cerebrospinal fluid analysis showed a mild lymphocytic pleocytosis (12) with normal RBC, protein, glucose, negative meningitis/encephalitis PCR, cytology and autoimmune encephalitis antibodies. Serum testing was negative for HIV, RPR, NMO, MOG and antinuclear antibodies. Working diagnosis of acute disseminated encephalomyelitis was made and he was started on IV methylprednisolone 1g daily for 5 days followed by an oral steroid taper with a weekslong improvement in symptoms to his neurologic baseline followed by relapse. We repeated MRI brain which demonstrated mixed response to treatment and two repeat CSF analyses showed 2 WBC with negative cytology. Given symptom recurrence, 1g daily IV methylprednisolone was re-administered for 5 days with another brief improvement, followed by IVIG 2g/kg over 5 days. Despite aggressive immunotherapy, his symptoms continued to worsen, and he was referred for brain biopsy confirming the diagnosis of primary diffuse large B-cell lymphoma of the CNS. At the direction of neuro-oncology, the patient underwent 6 cycles of systemic high-dose methotrexate and rituximab and 2 cycles of temozolomide with PET/MRI evidence of complete response (no lesion enhancement). His performance status improved significantly, and he underwent autologous hematopoietic stem cell transplant for consolidative therapy. <h3>Conclusions:</h3> CNS lymphoma should be considered in the differential for contrast-enhancing FLAIR hyperintensities and can be steroid responsive. Brain biopsy should not be delayed in cases where CNS lymphoma is a leading differential as it can guide early disease management and help improve patient outcomes. <b>Disclosure:</b> Dr. Frank has nothing to disclose. Dr. Alalami has nothing to disclose. An immediate family member of Dr. Livingston has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. An immediate family member of Dr. Livingston has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi. The institution of an immediate family member of Dr. Livingston has received research support from Vertex. The institution of an immediate family member of Dr. Livingston has received research support from Roche. The institution of an immediate family member of Dr. Livingston has received research support from AstraZeneca. The institution of an immediate family member of Dr. Livingston has received research support from Enanta. Dr. Hu has nothing to disclose. Dr. Shadbehr has nothing to disclose.

Extensive Central Nervous System Lymphoma Detected at the Time of Diagnosis of Chronic Lymphocytic Leukemia - An Isolated Central Nervous System Richter’s Syndrome: A Case Report

When a central nervous system (CNS) lesion is found in patients with chronic lymphocytic leukemia (CLL), the diagnostic possibilities include CNS involvement of CLL, transformation to a large B-cell lymphoma (Richter’s syndrome [RS]), or the coincidental presence of another tumorous or non-tumorous disease. CNS RS commonly occurs in preexisting CLL with other nodal/extra-nodal involvement, but it is extremely rare to find isolated CNS RS concurrently with the initial diagnosis of CLL. A 73-year-old woman presented with a headache and findings from another hospital of an elevated white blood cell count and intraventricular masses. A peripheral blood smear and a bone marrow biopsy revealed CLL. Brain magnetic resonance imaging with gadolinium enhancement showed a suprasellar mass and a pineal mass within the third ventricle, as well as extensive leptomeningeal enhancement. Whole-body fluorodeoxyglucose proton emission tomography-computed tomography showed no hot uptake except for the brain lesions. Cerebrospinal fluid cytology showed small atypical lymphocytes suggestive of CLL involvement. However, an endoscopic biopsy of the third-ventricle mass demonstrated diffuse large B-cell lymphoma. After 3 months of systemic high-dose methotrexate, all preexisting lesions disappeared, but new hemorrhagic masses were found in the right lateral ventricle and the fourth ventricle. The patient received palliative cranial radiotherapy but died 6 months after the initial diagnosis. Accurate CNS tissue diagnosis and appropriate treatment are critical.

Diagnosis, treatment, and prognosis of primary intraocular lymphoma: Single-center real-world clinical experience.

The diagnosis and management of primary intraocular lymphoma (PIOL) remain challenging. This study identified factors indicative of PIOL, described treatment outcomes, and determined modalities to prevent relapse. We included 21 PIOL-diagnosed patients, seven via cytology, 12 via genetic evaluation, and two via interleukin (IL) level measurements, who underwent vitrectomy and received local intravitreal methotrexate (IV-MTX) injection. Clinical outcomes, including treatment response and relapse, were compared between patients receiving IV-MTX alone (n=13) or IV-MTX with systemic high-dose methotrexate (HD-MTX) as prophylaxis (n=8). Twelve ophthalmologic and eight central nervous system (CNS) relapse cases within a median of 20.3 and 11.6 months were shown, regardless of the treatment modalities, with a median progression-free survival of 21.3 (95% confidence interval, 9.5-36.7) months. There was no difference in demographic characteristics between the two groups, except with the poorer performance status in patients in the HD-MTX prophylaxis group. Furthermore, patients demonstrated rapid elevations in the vitreous fluid IL-10/IL-6 cytokine ratio before ophthalmologic and CNS relapse. Therefore, diagnosis should be based on clinical signs and assisted by vitrectomy, cytologic, molecular, and cytokine studies. For PIOL, aggressive systemic treatment equivalent to that of primary CNS lymphoma (PCNSL) is recommended because solely HD-MTX did not prevent or delay CNS relapse. To prevent PIOL relapse in the CNS efficiently, prospective trials with large numbers of patients and advanced therapeutic regimens are necessary. Furthermore, regular clinical follow-up is crucial, and the IL-10/IL-6 ratio can help evaluate relapse promptly.

Long-term outcomes of combined intravitreal methotrexate and systemic high-dose methotrexate therapy in vitreoretinal lymphoma.

The optimal treatment for vitreoretinal lymphoma (VRL) remains a challenge, as central nervous system (CNS) relapse occurs frequently, leading to the worst impact on survival. We previously proposed combined intravitreal methotrexate and systemic high-dose methotrexate therapy for this disease. This study aimed to report the long-term outcomes of patients with VRL using this combination treatment. We conducted a retrospective cohort study on patients with VRL at a tertiary referral center between 2003 and 2018. Thirty-two patients were included, of whom 23 had primary VRL (PVRL) and nine had concurrent intraocular and CNS diseases. The treatment was well tolerated. Twenty-six (81.3%) patients achieved complete response (CR). After a median follow-up time of 103.5 months, the 5-year survival rate was 73.3%, whereas the 5-year progression-free survival (PFS) rate was 29.9%. Twenty-four (75%) patients relapsed, including 12 with isolated intraocular relapses at first relapse and a total of 17 with CNS/systemic relapses. The development of CNS/systemic relapse negatively affected survival, but intraocular relapse did not. The median CNS/systemic PFS was 69.5 months, but the risk of CNS/systemic relapse increased steadily with a cumulative incidence rate at 2, 5, and 10 years being 22.6%, 44.2%, and 65%, respectively. Multivariate analysis identified concurrent CNS disease at diagnosis as the only poor-risk factor for CNS/systemic relapse. This study confirms good efficacy and acceptable toxicities of the combination approach. However, incorporation of further intensive consolidation strategies into the treatment protocol to effectively prevent subsequent CNS/systemic relapse deserves to be considered.

Impact of BCL2/MYC Protein Dual Expression and Other Clinical Factors on the Risk of Central Nervous System Progression in Patients with Primary Breast Diffuse Large B-Cell Lymphoma

Background Primary breast diffuse large B-cell lymphoma (DLBCL) has poor outcomes with frequent extranodal failures, particularly in the central nervous system (CNS). Recent studies have reported that cell-of-origin (COO), BCL2/MYC dual expression (DE), and MYC and BCL2 and/or BCL6 rearrangements, so-called double hit (DH) and triple hit, are associated with a high risk of CNS progression in DLBCL; however, the impact of these biologic markers in primary breast DLBCL on CNS progression remains unknown. Methods CNS progression was analyzed in newly diagnosed primary breast DLBCL patients identified from 2 sources: the prospective study of the Consortium for Improving Survival of Lymphoma (CISL) study group conducted from January 2012 to July 2017, and the retrospective cohort included patients who were treated outside clinical trial at any CISL institutions between January 2012 and December 2020. Briefly, the prospective study (Yhim HY et al. Cancers 2020;12:2192) included 33 patients (20-75 years of age) with primary breast DLBCL, and treatment consisted of 6 cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and 4 doses of intrathecal (IT) methotrexate (MTX) at a 3-week interval. The eligibility criteria for the retrospective cohort were virtually the same as the prospective cohort, except for no age limit. 26 patients were screened, 6 of whom were excluded because of incomplete data (n=4) and secondary breast DLBCL (n=2). Thus, the retrospective cohort included 20 patients treated with 6 cycles of R-CHOP ± radiotherapy. CNS prophylaxis was not considered for eligibility in this cohort but was done in 17 patients (4-6 doses of IT MTX [n=14] and systemic high-dose MTX [n=3]). Expert hematopathologists centrally assessed COO and DE status. COO was determined using the Hans algorithm. MYC (≥40%) and BCL2 (≥50%) protein expressions were used to assign DE. Fluorescence in situ hybridization testing was used to determine DH lymphoma. The risk of CNS progression was estimated using the cumulative incidence method. The impact of variables of interest on CNS progression was assessed using a multivariable Cox model. Results We identified 53 patients from 2 data sources. The median age was 55 years (range, 29-78), and all were female. Most patients had unilateral (n=50, 94%), localized-stage (n=48, 91%), and ECOG performance status ≤1 (n=51, 95%). Serum LDH level was elevated in 14 (26%). Hence, IPI and CNS-IPI risks were mainly low (n=45, 85%). No patients had CNS disease at diagnosis. With a median follow-up of 58.8 months (IQR, 30.3-72.9), 7 patients developed CNS progression (parenchymal only, n=4; leptomeningeal only, n=2; parenchymal and leptomeningeal, n=1). The 4-year cumulative incidence of CNS progression was 15.6% (95% CI, 6.7-27.9; Fig A). The Cox analysis revealed bilateral breast involvement (HR, 9.39; 95% CI, 1.69-52.18) was an independent factor for CNS progression in this population. Of the 53 patients, 36 were selected as a histologic data-available population because of a lack of diagnostic materials for COO and DE in 17 patients. Baseline characteristics of the histologic data-available population (n=36) were similar to the overall population (n=53). In the 36 patients with histologic data available, 4 patients had CNS progression (parenchymal only, n=2; leptomeningeal only, n=1; parenchymal and leptomeningeal, n=1), and the 4-year CNS progression rate was 14.2% (95% CI, 0.4-26.3; Fig B). According to the Hans algorithm, 30 (83%) and 6 (17%) were classified as having non-GCB and GCB, respectively. 14 patients (39%) had BCL2/MYC DE, of whom 13 were non-GCB subtype (Fig C). The CNS progression rate of non-GCB did not differ significantly from that of the GCB subtype (4-year, 17.4% vs. 0%; p=0.326), but BCL2/MYC DE had a higher risk of CNS progression than non-DE (4-year, 30.7% vs. 0%, p=0.021; Fig D). 20 patients had sufficient tissue to test DH status, but no DH cases were identified. The multivariable Cox analysis of these 36 patients showed bilateral involvement (HR, 3.73; 95% CI, 1.28-10.86) and BCL2/MYC DE (HR, 2.42×104; 95% CI, 0.51×104-10.60×104) were independent predictors for CNS progression. Conclusion Our data suggested that bilateral breast involvement and BCL2/MYC DE were independent risk factors for CNS events in patients with primary breast DLBCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ABCL-455 Multicenter Retrospective Analysis of Single-Route Prophylaxis in Aggressive B-Cell Lymphomas

Relapses involving the central nervous system (CNS) are uncommon among patients with diffuse large B-cell lymphoma (DLBCL) but carry very poor prognosis. Prophylaxis is heterogeneously prescribed around the time of frontline therapy, with no clear standard of care in terms of recipient selection or route of administration. We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline chemoimmunotherapy between 2013-2019. Primary endpoint was CNS relapse rate. Secondary endpoints included PFS, OS, and treatment-related toxicities following frontline and salvage therapies. Prophylaxis was administered intrathecally (IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%). Sixty-four patients (5.7 %) had CNS relapse, after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4 vs 6.8%, p=0.40), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected versus observed CNS relapse rates were nearly identical (5.8 vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. Median OS following CNS relapse was 6.2 months (IQR 2.9-24.6) and was significantly shorter among patients achieving less than CR to first salvage therapy (HR 3.39, 95% CI 1.76-6.54, p=0.0003). Additional analyses of outcomes following CNS relapse will be presented. This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated; treatments following CNS relapse were heterogeneous, with poor outcomes for the vast majority of patients. Reconsideration of SCNSL prophylaxis and treatment strategies is of critical need.

Ibrutinib in Combination with Rituximab and High-Dose Methotrexate in Newly Diagnosed Primary Central Nervous System Lymphoma Patients

Ibrutinib in combination with rituximab and high-dose methotrexate in newly diagnosed primary central nervous system lymphoma patientsYixian Guo, Xiaoxi Lan, Xiaoli Chang, Guoxiang Wang, Dongmei Zou, Li Su, Wanling SunDepartment of Hematology, Xuanwu Hospital, Capital Medical University, Beijing 100053, P.R. ChinaCorresponding author: Wanling Sun, M.D. & Ph.D.Email: wanlingsun@xwhosp.orgBackground: Primary central nervous system lymphoma (PCNSL) is a rare extranodal lymphoma. Most PCNSL are pathologically classified as diffuse large B-cell lymphoma (DLBCL). In addition to the importance of high-dose systemic methotrexate (HD-MTX), there is no consensus on the optimal composition of induction and consolidation therapy for newly diagnosed PCNSL. BTK inhibitors are the second-line recommended choice in relapsed of refractory cases. In this study, we described our institutional experience with the oral BTK inhibitor, ibrutinib, combined with rituximab and HD-MTX (I-RM regimen) in newly diagnosed PCNSL. This study is registered with Chictr.org.cn, number ChiCTR1900027811.Methods: The study was a phase 1, investigator-initiated, clinical trial being conducted at Xuanwu Hospital, Capital Medical University . Patients definitely diagnosed as PCNSL-DLBCL by biopsy of brain lesion, systemic imageology, bone marrow and CSF examination, et al, and be suitable for the immunochemotherapy,were enrolled the clinical trial. The next-generatioin sequencing of the lesion tissue were used to detect hot spot mutations evolved in B cell lymphoma. The ibrutinib-based I-RM regimen consists of rituximab 375mg / m 2 on day 0, MTX 3.5g/m 2 on day1, and ibrutinib 560mg once daily starting from plasma MTX concentration <0.1umol/L to day 28, every 28 days is a cycle of treatment. After 4 cycles of I-RM induction therapy, patients who achieved CR/CRu/PR received autologous peripheral blood hematopoietic stem cell transplantation (HSCT) or the extra 2 cylces of I-RM regimen as consolidation therapy. Ibrutinib or lenalidomide monotherapy was prescribed as maintenance therapy, according to the willingness of patients until the disease progresses. The primary end point was the safety and efficacy of this regimen in newly diagnosed PCNSL.Results:There were totally16 patients enrolled in this clinical trial, between April 2018 and December 2020 (Table 1). All the patients were pathologically DLBCL, including 14 non-GCB subtypes and 2 GCB subtypes. The commonest hot spot mutations were PIM1 (68.75%), MYD88 (43.75%), and CD79B (37.50%). The median follow-up time was 24.5 (6-37) months up to June 30, 2021. After 4-cycles of I-RM induction therapy, CR were achieved in 8 patients (50%), PR in 7 patients (44%), and progressive disease in one patients(6%) who quit the clinical trial and transferred to other regimen，and the ORR of induction therapy was 94%. Among 15 responsers, 5 (33%) received HSCT and 10 (67%) received extra 2 cylces of I-RM regimen as consolidation therapy. After the consolidation therapy, 93% patients (14/15) received maintenance therapy, including 6 received lenalidomide and 8 received ibrutinib. Relapse happened in 2 patients during the maintenance therapy, including 1 death due to the progressed disease (Table 2). The median PFS and OS were not achieved, and the estimated 3-year OS and PFS were 88.9% and 86.5%, respectively (Figure 1). No grade 4 adverse event was observed. The grade 3 hematologic toxicities included lymphopenia in 3 cases and neutropenia in 1 case .The grade 3 non-hematologic toxicities including hypertension in 1 case and increased serum creatinine in 1 case.Conclusions: Our data preliminarily indicates that I-MR is active and safe as a first-line regimen in newly diagnosed PCNSL and might effectively improve the survival of these patients. More patients and longer follow-up are needed to confirm our conclusion. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Functional CRISPR Screening Identifies Ptprg As a Driver of Migration and Adhesion in NSD2-E1099K ALL

Background: Acute Lymphoblastic Leukemia (ALL) is the most common childhood cancer and frequently infiltrates the central nervous system (CNS). CNS-directed therapy is currently limited to intrathecal and systemic high-dose methotrexate, or less commonly craniospinal irradiation, both of which are associated with substantial neurotoxicity. A lack of mechanistic understanding of the mechanisms of CNS infiltration presents an obstacle for the development of more specific and less toxic therapeutic approaches. We previously showed that ALL cells with a specific mutation (E1099K) in the histone methyltransferase NSD2 have aggressive CNS tropism by not only infiltrating the leptomeninges but also the brain parenchyma in murine xenografts models. Analysis of cBioPortal data shows that NSD2-E1099K is associated with a higher rate of testicular involvement in ALL also suggesting more aggressive infiltration behavior of the tumor. Accordingly, using gene editing to revert mutant NSD2 back to wild-type, we also showed that NSD2-E1099K cells have an enhanced ability to migrate and adhere in vitro. RNA-seq data on four NSD2-E1099K cell lines revealed genes that may play a role in ALL brain infiltration. However, it remains unknown which of those upregulated genes could be potential therapeutic targets against CNS leukemia.Aim: This study aims to Identify therapeutically targetable genes that are important for migration of NSD2-E1099K ALL cellsMethods: Using a focused CRISPR-gene-knockout library of 5600 sgRNAs directed against 500 genes upregulated in NSD2-E1099K cells, we ascertained the necessity of the selected genes for migration in the RCH-ACV cell line. Candidate genes were evaluated for cellular dependency using a CRISPR-loss of function screen and the cancer dependency map portal. Overexpression of the candidate genes in NSD2-E1099K cell lines was confirmed with qPCR analysis. Candidate genes were validated by individual shRNA knockdown followed by migration and adhesion assays.Results: Our study identified genes whose knockout led to enhancement of migration and others whose knockout resulted in inhibition of migration. Protein Tyrosine Phosphatase Receptor Type G (PTPRG) was one of the top candidate genes whose knockout resulted in inhibition of migration. Dependency map analysis showed that PTPRG is not a commonly essential gene and a CRISPR-based-loss-of function screen performed in parallel to the migration screen confirmed that ALL cell survival is not dependent on PTPRG. We also found that PTPRG is overexpressed in multiple NSD2-E1099K ALL cell lines. Individual Knockdown of PTPRG in NSD2-E1099K ALL cell lines not only inhibited migration, but also led to a loss of adhesion ability to endothelial cells of the Blood Brain Barrier.Conclusions: Our findings implicate PTPRG as an important modulator of migration and adhesion in ALL cells and a potential therapeutic target for preventing ALL brain infiltration, especially in NSD2-E1099K ALL. DisclosuresLicht: Epizyme: Research Funding.

Single-route CNS prophylaxis for aggressive non-Hodgkin lymphomas: real-world outcomes from 21 US academic institutions

AbstractProphylaxis is commonly used to prevent central nervous sy stem (CNS) relapse in diffuse large B-cell lymphoma (DLBCL), with no clear standard of care. We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline therapy between 2013 and 2019. Prophylaxis was administered intrathecally(IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%). Sixty-four patients (5.7%) had CNS relapse after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4% vs 6.8%, P = .4), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected vs observed CNS relapse rates were nearly identical (5.8% vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated, and reconsideration of prophylaxis strategies in DLBCL is of critical need.

The Efficacy of Systemic High Dose Methotrexate As Central Nervous System Prophylaxis in Patients with High Risk Diffuse Large B-Cell Lymphoma: A Propensity Score-Matched Analysis

Background: While the outcome of patients with diffuse large B-cell lymphoma (DLBCL) has been improved with the introduction of rituximab, central nervous system (CNS) relapse is still associated with poor prognosis. Although intrathecal methotrexate has been widely used for prophylaxis, its role has been questioned. Another way of utilizing the agent, systemic high dose methotrexate (HD-MTX) has been advocated from a few retrospective studies. However, they had no comparison group or they were compared with imbalanced, unmatched group even if existed. With prospectively collected cohort, we performed a propensity score-matched analysis to evaluate the efficacy of IV HD-HTX as CNS prophylaxis in high risk DLBCL patients.Methods: The registry data set of DLBCL patients, collected from January 2010 through March 2015 at a single institute, Asan Medical Center, was retrospectively reviewed. From July 2013, all consecutive DLBCL patients who were considered at high risk for CNS recurrence received systemic HD-MTX with standard R-CHOP therapy. High risk CNS relapse was defined by the involvement of ≥2 extranodal sites and elevated lactic dehydrogenase (LDH); or high-risk CNS international prognostic index (CNS-IPI ≥4); or involvement of specific high-risk extranodal sites including bone marrow, breasts, testes, paranasal sinuses. HD-MTX was administered at a dose of 3-3.5 g/m2 on day 15 of alternating cycles of R-CHOP or delivered 2 to 5 weeks after the completion of the primary therapy. We analyzed the progression-free survival (PFS), CNS relapse-free survival (CNS-RFS) and overall survival (OS) of the patients receiving CNS prophylaxis and compared with the patients who received R-CHOP only. Multivariate Cox regression and propensity score analysis were used to evaluate the treatment effect of systemic HD-MTX on survival with multiple covariates including age, sex, LDH, ECOG score, stage, CNS-IPI, extranodal involvement and involved sites.Results: A total of 197 patients with DLBCL and CNS risk factors who were treated with standard R-CHOP therapy were identified between January 2010 and March 2015. Among them, 47 patients received systemic HD-MTX as CNS prophylaxis. In the R-CHOP only group (n=150), with a median follow-up of 58.88 (1.34-84.3) months, 14 CNS relapses occurred within 2 years. The estimated 2-year PFS, CNS-RFS and OS rates were 58.6%, 89.5%, 71.3%, respectively. In the HD-MTX prophylaxis group (n=47), with a median follow-up of 27.24 (3.38-42.02) months, 3 CNS relapses occurred within 2 years. The estimated 2-year PFS, CNS-RFS and OS rates were 62.3%, 93.1% and 74.5%, respectively. Systemic HD-MTX did not significantly increase the PFS (HR 0.619, 95% CI 0.363-1.057, P = .079), CNS-RFS (HR 0.547, 95% CI 0.156-1.924, P=.347), and OS (HR 0.628, 95% CI 0.331-1.19, P = .154) in the multivariate survival analysis. The results seems to consistently show no survival benefit of systemic HD-MTX regardless of the different propensity score analysis methods except for PFS by weighting HR: PFS (matching HR 0.652, 95% CI 0.36-1.18, P=.157; weighting HR 0.689, 95% CI 0.503-0.945, P=.02),CNS-RFS (matching HR 0.635, 95% CI 0.161-2.499, P=.516; weighting HR 0.587, 95% CI 0.287-1.203, P=.146), OS (matching HR 0.625, 95% CI 0.319-1.227, P=.172; weighting HR 0.726, 95% CI 0.505-1.044, P=.083).Conclusion: Systemic HD-MTX prophylaxis for CNS relapse did not show significant survival improvement in high risk DLBCL patients in this study although there was a trend for better outcomes in patients given HD-MTX, as different statistical methods incorporating stringent propensity score-matched analysis were applied. However, these results are still limited by small cohort size its retrospective nature. Multi-center, prospective randomized studies are necessary to appraise the efficacy of systemic HD-MTX as CNS prophylaxis in high risk DLBCL patients. DisclosuresNo relevant conflicts of interest to declare.

Real-World Data (RWD) on the 3-Year Follow-Up Outcomes of Different CNS Prophylaxis Strategies Across CNS-IPI Risk Groups in Patients With Diffuse Large B-Cell Non-Hodgkin Lymphoma.

PURPOSECNS relapse in patients with diffuse large B-cell lymphoma (DLBCL) is associated with poor prognosis with a median survival of about 2.5 months. Data demonstrating best prophylactic strategy remain controversial and need further definition.PATIENTS AND METHODSWe present data of 110 patients with DLBCL treated with standard systemic therapy divided into four groups based on primary CNS prophylaxis strategy and CNS International Prognostic Index (IPI) risk categories. We compared their 3-year CNS relapse rate and overall survival in each group.RESULTSThe CNS prophylaxis strategy consisted of intrathecal (IT) methotrexate (MTX) in group 1, high-dose (HD) MTX in group 2, combination IT and HD MTX in group 3, and IT and/or HD MTX with intensive chemotherapy in group 4. At 3 years, CNS relapse rate was 8.6% (4/46), 8.3% (1/12), 4.8% (2/42), and 18% (2/11) in groups 1-4 (P = .64), respectively. According to CNS IPI, the CNS relapse rate was 16.6%, 10.1%, and 0% in high-, intermediate-, and low-risk groups, respectively. The 3-year overall survival rate was 69%, 75%, 80%, and 45% in groups 1-4 (P = .71), respectively.CONCLUSIONOur study while did not find statistical significance did indicate a lower incidence of CNS relapse with the addition of systemic HD MTX to IT MTX in the high-risk DLBCL population.

Ambulatory high-dose methotrexate administration as central nervous system prophylaxis in patients with aggressive lymphoma

High-dose methotrexate (HD-MTX) at 3 g/m2 is one of the strategies for central nervous system (CNS) prophylaxis in the first-line treatment of aggressive lymphomas, especially in diffuse large B cell lymphoma patients with high-risk CNS-International Prognostic Index. The objective of our study was to retrospectively analyze the safety of 2 cycles of systemic HD-MTX administered as an ambulatory regimen. Between January 2013 and December 2016, 103 patients were carefully selected on 6 criteria, including age < 60, albumin > 34, performance status 0 or 1, normal renal and hepatic functions, good understanding of practical medical guidance, and no loss of weight. Strict procedures of HD-MTX infusion were observed including alkalinization, urine pH monitoring, and leucovorin rescue. Renal and hepatic functions were monitored at days 2 and 7. MTX clearance was not monitored. Toxicities and grades of toxicity were collected according to the NCI-CTCAE (version 4.0). Among the 103 selected patients, 92 (89%) patients successfully completed the planned 2 cycles of HD-MTX on an outpatient basis. Eleven patients completed only 1 cycle, 3 because of lymphoma progression and 8 because of toxicity including 3 grade II hepatotoxicity, 2 grade I/II renal toxicity, 1 grade III neutropenia, 1 active herpetic infection, and 1 grade III ileus reflex. Reported adverse events (AE) included 92 (84%) grade I/II and 18 (16%) grade III/IV. Grade III hepatotoxicity, mostly cytolysis, was the most frequent AE observed with 8 (8%) events. Grade III/IV hematologic toxicities concerned 9 patients with 8 grade III/IV neutropenia and 1 thrombocytopenia. Renal toxicity was rare, mild, and transient, observed with 4 (4%) grade I/II events. Ambulatory administration of HD-MTX at 3 g/m2 without MTX clearance monitoring is safe with strict medical guidance. It requires careful selection of patients before administration, and a renal and hepatic monitoring after the administration.

Systemic vs. intrathecal central nervous system prophylaxis in primary adrenal/renal diffuse large b-cell Lymphoma: A multi-institution retrospective analysis and systematic review

Primary adrenal lymphoma (PAL) and primary renal lymphoma (PRL) are rare extranodal lymphomas, predominantly of diffuse large B-cell lymphoma subtype. Primary adrenal and renal lymphomas (PARL) exhibit a high predilection for the central nervous system (CNS). Therefore, current guidelines support the use of CNS prophylaxis in PARL, particularly in cases of high-risk Central Nervous System International Prognostic Index (CNS-IPI). However, the route of administration (i.e. systemic vs. intrathecal chemotherapy) has not been clearly elucidated. With this in mind, we initiated an international collaboration and literature review to analyze 50 patient cases, 20 of whome received CNS prophylaxis. Based on our analysis, we conclude that PARL may indicate a need for CNS chemo-prophylaxis in the form of systemic high-dose methotrexate (HD-MTX) over intrathecal methotrexate (IT-MTX), although IT-MTX may still have utility in certain cases.

Intensive Treatment of Children With Acute Lymphoblastic Leukemia According to ALL-BFM-86 Without Cranial Radiotherapy: Results of Dutch Childhood Leukemia Study Group Protocol ALL-7 (1988-1991)

AbstractIn The Netherlands from July 1988 to October 1991, children (0 to 16 years of age) with de novo acute lymphoblastic leukemia (ALL) were treated according to protocol ALL-7 of the Dutch Childhood Leukemia Study Group (DCLSG). In this protocol, chemotherapy and treatment stratification were identical to the ALL-BFM-86 protocol (Reiter et al, Blood 84:3122, 1994), but cranial irradiation was restricted to patients with initial central nervous system (CNS) involvement. Patients were stratified into 3 risk groups, based on leukemia cell mass and response to initial treatment: standard-risk group (SRG), risk group (RG), and experimental group (EG). As in ALL-BFM-86, a randomized study on late intensification (protocol S) was performed in RG patients, and during the study (since October 1990), early reinduction treatment (protocol II) was introduced for SRG patients. Treatment duration for all patients was 18 months. Two hundred eighteen children entered the study: 74 SRG, 127 RG, and 17 EG patients. The overall complete remission (CR) rate was 98%. The 5-year event-free survival (EFS) for all DCLSG ALL-7 patients was 65.3% (standard error [SE] 3.2%), which was significantly different from the 73% (SE 1%) 5-year EFS achieved in the ALL-BFM-86 study (P = .02, Z-test). However, restricting the analysis to SRG patients receiving protocol II with a total duration of treatment of 18 months, the 5-year EFS rates were 64.6% (SE 4.0%) and 67% (SE 4%), respectively, and no significant difference could be established (P = .67, Z-test). The 5-year EFS rates for SRG, RG, and EG patients were 63.5% (SE 5.6%), 66.6% (SE 4.2%), and 63.3% (SE 12.0%), respectively. SRG patients receiving protocol II fared better than patients not receiving protocol II (5-year EFS 76.7% [SE 7.7] and 54.5% [SE 7.5], respectively). No difference in 5-year EFS was observed in RG patients randomized to receive or not to receive late intensification with protocol S. The overall CNS relapse rate at 5 years was 5.5%. The incidence rate at 5 years was 11.4% in SRG patients not receiving protocol II, whereas no CNS relapses occurred in SRG patients receiving protocol II. Six children died in first complete remission and 2 children developed a second malignancy (thyroid carcinoma and acute nonlymphoblastic leukemia). Systemic high-dose methotrexate (MTX) and intrathecal chemotherapy is a safe and effective method of CNS prophylaxis in the context of BFM-oriented treatment for all children with ALL, regardless of the risk group (with the possible exception of T-ALL patients with high white blood cell counts). The results of the DCLSG ALL-7 study confirm those of the ALL-BFM-86 study showing that early reinduction with protocol II is essential in the treatment of SRG patients and that late intensification with protocol S does not improve the prognosis for RG patients.

Impact of central nervous system (CNS) prophylaxis on the incidence of CNS relapse in patients with high-risk diffuse large B cell/follicular grade 3B lymphoma

Although overall survival in diffuse large B cell lymphomas (DLBCL) has improved, central nervous system (CNS) relapse is still a fatal complication of DLBCL. For this reason, CNS prophylaxis is recommended for patients at high risk of CNS disease. However, no consensus exists on definition of high-risk patient and optimal CNS prophylaxis. Systemic high-dose methotrexate in combination with R-CHOP has been suggested as a potential prophylactic method, since methotrexate penetrates the blood-brain barrier and achieves high concentration in the CNS. In this retrospective analysis, we report treatment outcome of 95 high-risk DLBCL/FL grade 3B patients treated with R-CHOP or its derivatives with (N = 57) or without (N = 38) CNS prophylaxis. At a median follow-up time (51 months), CNS relapses were detected in twelve patients (12.6%). Ten out of twelve (83%) of CNS events were confined to CNS system only. Median overall survival after CNS relapse was 9 months. Five-year isolated CNS relapse rates were 5% in the prophylaxis group and 26% in the group without prophylaxis. These findings suggest that high-dose methotrexate-containing prophylaxis decreases the risk of CNS failure.

Long-term clinically relevant rodent model of methotrexate-induced cognitive impairment.

With the enhanced use of chemotherapy and the advent of increased patient survival rates, there are an increasing number of cancer survivors living with chemotherapy-induced cognitive impairment. A growing number of clinical studies have brought to light the association of agents like methotrexate in generating these neurological sequelae, although mechanisms remain unclear. Here, we use a clinically relevant regimen of several cycles of methotrexate and leucovorin rescue to develop a model of chemotherapy-induced cognitive impairment, and investigate the in vivo long-term (16 mo) impact of high-dose systemic methotrexate on white matter cellular dynamics as assessed by stereology, animal behavior, and diffusion tensor imaging. Our results indicate that at 6 and 16 months post-chemotherapy, methotrexate-treated rats exhibit a significant and permanent decrease in the number of oligodendrocytes and their progenitors in the white matter, in corpus callosum volumes, and myelin basic protein. These findings are associated with mostly delayed deficits in performance on Morris Water Maze and Novel Object Recognition tasks. Diffusion tensor imaging demonstrates significantly decreased fractional anisotropy values in the callosum genu, body, and splenium, as well as previously unassessed areas like the fimbria. Interestingly, these white matter changes are preceded by an earlier, transient decrement in white matter microglia at 3 months, and hippocampal neural progenitors at 3 and 6 months. These results demonstrate a significant negative impact of methotrexate on the oligodendrocyte compartment and white matter, associated with cognitive impairment. The data also support the use of diffusion tensor imaging in monitoring white matter integrity in this context.

HDMTX-based polychemotherapy including intraventricular therapy in elderly patients with primary CNS lymphoma: a single center series.

Background:To investigate outcome and toxicity of high-dose systemic methotrexate (HDMTX)-based polychemotherapy and intracerebroventricular (ICV) chemotherapy via an Ommaya reservoir in elderly patients with primary central nervous system lymphoma (PCNSL).Methods:We performed a retrospective analysis on patients ⩾65 years with first diagnosis of PCNSL admitted to our center between January 2015 and December 2019. These patients were treated with a standardized chemotherapy protocol in case of absent contraindications for HDMTX-based chemotherapy. The protocol contained induction therapy with systemic rituximab, methotrexate and ifosfamide and consolidation treatment with systemic cytarabine (AraC) and ICV methotrexate, prednisolone and AraC.Results:Of a total of 46 patients seen in this period, 3 did not qualify for HDMTX. Thus, 43 patients were included in this analysis. Median age was 74 years (range 65–86), median Karnofsky performance score was 50 (range 20–90). Of the 43 patients, 32 (74.4%) completed treatment including ICV therapy. Complete remission/complete remission unconfirmed was achieved in 26 of 43 patients (60.5%), partial response (PR) in 3 (7%); 5 (11.6%) had progressive disease, and 3 (7.0%) died due to treatment-related complications; in the remaining 6 (14.0%) therapy could not be completed. Median progression free survival was 16 months (95% confidence interval 8–24 months) and median overall survival had not been reached after a median follow up of 23 months (range 1–52 months); the 75th percentile survival time was 12 months. No Ommaya reservoir infection was observed. Complications of ICV treatment were pericatheter leucencephalopathy in two patients and surgical scar dehiscence with cerebrospinal fluid leak in one patient.Conclusion:Toxicity of HDMTX plus ICV chemotherapy for elderly patients with PCNSL was manageable and outcome was excellent for patients treated with this protocol.

S5-KL-1 CURRENT TREATMENT FOR DLBCL AND PROPHYLAXIS AND TREATMENT FOR SECONDARY CNS LYMPHOMA

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of lymphoma, comprising 30% of all lymphoma cases. More than 60% of patients can be cured with current standard treatment, R-CHOP. On the other hand, prognosis of patients with relapsed or refractory DLBCL is disappointing with less than 10% being cured with salvage chemotherapy followed by high-dose chemotherapy with autologous stem cell transplantation. Prognosis of patients with central nervous system (CNS) relapse is especially poor because of a limited treatment option. Thus, evaluating risks of CNS relapse at diagnosis and administering prophylaxis including intrathecal methotrexate (MTX) or systemic high-dose MTX concurrently with R-CHOP or as consolidation therapy in high-risk patients are often-used approach. Clinically, higher risk according to the International Prognostic Index and extranodal involvement in organs such as kidney, adrenal gland, breast, testis, or bone marrow are considered to be high-risk for CNS relapse. Recently, CNS-International Prognostic Index has been proposed to integrate aforementioned risk factors. Moreover, patients with intravascular large B-cell lymphoma, CD5+ DLBCL, double hit lymphoma are reported as high-risk for CNS relapse. Further, the MYD88 L265P mutation, a common mutation in primary CNS DLBCL (PCNSL) is also common in DLBCL of testis or breast, which are the sites associated with CNS relapse.Strategies for CNS prophylaxis have not established yet, and it is still unclear whether intrathecal MTX or high-dose MTX can prevent CNS relapse. Moreover, treatment for secondary CNS relapse have not been established. In particular, for those with both CNS and extra-CNS lesions, effective treatment options are very limited. The role of novel agents such as BTK inhibitors, lenalidomide, and immune check point inhibitors, whose efficacy have been shown for PCNSL, should be investigated further in the management of secondary CNS lymphoma.

Central Nervous System Prophylaxis Is Required and Associated with a Prolonged Overall Survival in Both Early and Advanced-Stage Primary Adrenal/Renal Diffuse Large B-Cell Lymphoma

Introduction Primary adrenal lymphoma (PAL) and primary renal lymphoma (PRL) are rare extranodal lymphomas, predominantly of diffuse large B-cell lymphoma (DLBCL) subtype. Adrenal/renal involvement is one of six risk factors that define the Central Nervous System International Prognostic Index (CNS-IPI), the most commonly used tool in determining the risk of CNS relapse in DLBCL. However, guidelines regarding CNS prophylaxis in early stage PAL/PRL (Ann Arbor IE and IIE) and advanced stages without high-risk CNS-IPI, and optimal route of administration have not been clearly elucidated. Here we provide an analysis of over 400 cases of PAL/PRL, the largest collection to date, including data on disease biology, risk of CNS relapse, CNS prophylaxis, and outcomes. Methods We conducted a comprehensive literature review on adult PAL/PRL cases reported from Jan 1st 1998 to July 1st 2019 in PubMed. Additionally, we collected cases available at our institution and through international collaborators. We excluded cases with CNS involvement at onset, unknown staging, and histology other than DLBCL. Data were tabulated regarding the following variables: age, gender, stage, laterality, cell-of-origin (germinal center B-cell-like (GCB) vs. activated B-cell-like (ABC)), chemotherapy, CNS prophylaxis (and type), CNS relapse, and overall survival (OS). OS was calculated using the Kaplan-Meier method, and comparison between OS curves made using the log-rank test, with statistical significance set as p-value &lt; 0.05. Results/ Discussion With over 700 PAL/PRL cases available for review, 405 met inclusion criteria (258 from PubMed, 147 through collaboration). Analyzing the fraction of reported cases, patients were predominantly advanced stage (68%; 274/405), male gender (77%; 167/218), older than 60 years (73%; 157/214), had bilateral involvement (70%; 130/186), and were of ABC cell-of-origin (69%; 101/146) (Fig. 1A). Only 45 patients had available CNS-IPI scores (13 low/intermediate and 32 high), which limits drawing strong conclusions. The low/intermediate-risk group did not have a CNS relapse event, with 46% (6/13) receiving CNS prophylaxis. The high-risk group had 22% (7/32) CNS relapse rate overall, with 21% (3/14) relapse among the CNS prophylaxis subset. For the CNS-IPI group overall, a strong correlation was noted between disease stage and CNS-IPI risk: 85% of the low-risk CNS-IPI group had early-stage disease (stages IE and IIE), and 84% of the high-risk IPI group had advanced stage. Therefore, we sought to examine the rate of CNS relapse and impact of CNS prophylaxis for early vs. advanced-stage PAL/PRL. CNS relapse was documented in 15% of all cases (60/405), but was notably higher in advanced stage (20%; 55/275) vs. early stage (4%; 5/131) disease (Fig. 1A). Intriguingly, CNS prophylaxis did not affect CNS relapse rate in the advanced-stage group (26% vs. 28% with prophylaxis), while in the early-stage group it was beneficial (17% vs. 0% with prophylaxis) (Fig. 1B). Nevertheless, CNS prophylaxis was associated with a prolonged OS regardless of the disease stage (Fig. 1C). We then analyzed whether type of CNS prophylaxis used - intrathecal methotrexate or cytarabine (IT-chemo) vs. high-dose systemic methotrexate (HD-MTX) with or without IT-chemo - affected OS and CNS relapse rate. The OS curve favored HD-MTX in a limited size of 26 cases (Fig. 1D). CNS relapse data was available in 35 cases. CNS relapse was not found with HD-MTX (0/10), while it was observed in 32% (8/25) of the IT-chemo group, all of which were advanced stage (8/20). This can explain, at least in part, the lack of difference in rate of CNS relapse between the prophylaxis and non-prophylaxis groups in the setting of advanced stage. Consequently, a strong trend toward a better OS (p=0.12) was observed when HD-MTX was used in the setting of advanced-stage disease. Conclusion PAL/PRL is a rare presentation of DLBCL, more likely to be associated with high-risk features such as ABC cell-of-origin and advanced-stage disease. CNS prophylaxis should be used regardless of disease stage, preferably with HD-MTX in the setting of advanced-stage disease. Given the close relationship between stage and CNS-IPI, our findings suggest that, akin to primary testicular DLBCL, PAL/PRL could be an independent and significant predictor for CNS relapse regardless of the CNS-IPI, implicating the need for CNS chemo-prophylaxis in all cases. Disclosures Ferreri: Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding. Safah:Amgen: Honoraria, Speakers Bureau; Incyte: Speakers Bureau; Jazz: Speakers Bureau; Verastem: Honoraria, Speakers Bureau; Celgene: Speakers Bureau. Saba:Pharmacyclics: Consultancy, Speakers Bureau; Kyowa Kirin: Consultancy; AbbVie: Consultancy; Janssen: Consultancy, Speakers Bureau.

Systemic high-dose intravenous methotrexate in patients with central nervous system metastatic breast cancer

BackgroundInfusion of high-dose intravenous methotrexate (MTX) has been demonstrating to penetrate the blood-brain barrier. The aim of this present study was to assess the efficacy and safety of high dose MTX in patients with central nervous system (CNS) metastases of breast cancer.MethodsTwenty-two patients with CNS metastases treated by MTX (3 g/m2) between April 2004 and October 2009 were enrolled. Clinical response rate, time to progression (TTP), overall survival (OS), and safety were assessed.ResultsIn terms of brain metastases, 2 patients (9%) achieved a partial response, 10 patients (45%) had disease stabilization, and 10 patients (45%) had disease progression. In others metastatic sites, 7 patients (39%) achieved a disease stabilization, and 11 patients (61%) had disease progression. TTP and OS were 2.1 (95%CI 1.4–2.9) and 6.3 (95%CI 1.8–10) months, respectively.ConclusionHigh-dose MTX demonstrated a moderate activity at 3 g/m2. Nonetheless, the favorable toxicity profile should suggest the possibility to increase the dosage and further study are planned.